1. Field of the Invention
The present invention generally relates to an improved process for the separation of a mixture of enantiomers of 5H-pyrrolo[3,4-b]pyrazine derivatives. More specifically, the present invention relates to a process for the preparation of dextrorotatory isomer of zopiclone by resolution of zopiclone by means of an optically active acid, in an appropriate organic solvent. The present invention also relates to a process for resolution of eszopiclone and salts thereof. The present invention further relates to a crystalline form of eszopiclone and process for its preparation.
2. Description of the Related Art
Eszopiclone, also known as the dextrorotary isomer of zopiclone or (+)-(5S)-6-(chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrol[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate) is represented by the structure of Formula I.
Eszopiclone is a nonbenzodiazepine hypnotic agent that is a pyrrolopyrazine derivative of the cyclopyrrololone class. Eszopiclone is indicated for the treatment of insomnia. Eszopiclone is commercially sold under the trade name Lunesta®. See, e.g., Physician's Desk Reference, “Lunesta” 60th Edition, p. 3139-3143 (2005).
French Patent No. 72.00505 (published under number 2.166.314) discloses zopiclone (also known as 6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine), which may act as a hypnotic product. Due to the presence of an asymmetric carbon atom at the 5-position of the 5H-pyrrolo[3,4-b]-pyrazine ring-system, zopiclone is considered to be in racemic form, that is, consisting of an equimolecular mixture of the laevorotatory and dextrorotatory forms.
It is known that in a racemic mixture, one of the two enantiomers is often more active than the other and that an enhancement of the toxicity may be linked to this activity. The other enantiomer is generally less active or even inactive and less toxic. For such products, the gain in activity does not compensate for the drawbacks due to the enhanced toxicity. In the case of zopiclone, it was found that not only was the dextrorotatory isomer approximately twice as active with lower toxicity as compared to the racemate, but that the laevorotatory isomer is both almost inactive and more toxic than the racemate.
U.S. Pat. No. 6,444,673 discloses processes for the preparation of the dextrorotatory isomer of zopiclone by resolving zopiclone with D(+)-O,O′-dibenzoyltartaric acid as an optically active acid in one or more organic solvents chosen from halogenated aliphatic hydrocarbons such as dichloromethane and nitriles such as acetonitrile.
Mixtures of enantiomers are obtained, for instance, in reactions that do not, or only to a small extent, proceed stereoselectively or in reactions in which there is no complete inversion or retention. The physical properties of enantiomers, such as boiling point, melting point and the like, are the same, so that a mixture of enantiomers cannot be separated using the customary separation techniques. In one of the methods for the separation of mixtures of enantiomers, an optically active resolving agent is used to convert both enantiomers into the corresponding diastereomers. As the physical properties of these diastereomers do differ, the diastereomers can, at any rate in principle, subsequently be separated by, for instance, crystallization or chromatography, both diastereomers being obtained in substantially chemically pure and optically enriched form. The diastereomer can in a third step again be separated into the corresponding, optically enriched enantiomer and the optically active resolving agent. Several processes and optically active resolving agents for the separation of enantiomers are, for example, extensively described in “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley Interscience), 1994).
As a result of the presence of an asymmetric carbon atom at the 5-position of the 5H-pyrrolo[3,4-b]-pyrazine ring-system, zopiclone must be considered, in racemic form, to consist of a strictly equimolecular mixture of the laevorotatory and dextrorotatory forms.
From the standpoint of the potency of action in the main tests demonstrating the tranquilizing and hypnotic activity of zopiclone, such as the test of affinity for central benzodiazepine receptor sites according to the technique of J. C. Blanchard and L. Julou, J. of Neurochemistry, 40, 601 (1983) based on the work of Squires and Braestrup, Nature, 266, 732-734 (1977), or the test of antagonist activity with respect to pentetrazol-induced convulsions according to the technique of Everett and Richards, J. Pharmacol., 81, 402 (1944), or in the writhing reflex test in mice according to the technique of Zbinden and Randall, Advances in Pharmacology 5, 213-291 (1967), the dextrorotatory isomer is approximately twice as active whereas the laevorotatory isomer is almost inactive.
It is common knowledge that finding the right resolving agent for the separation of mixtures of enantiomers by crystallization of a mixture of diastereomers is in practice a laborious and highly time-consuming process, for a correct choice of the resolving agent cannot in advance be made, not even when applying advanced techniques such as, for example, computer simulations or X-ray diffraction, and thus has to be found by trial and error for each mixture of enantiomers anew. This implies that for the separation of enantiomers via diastereomers often many experiments have to be conducted, while the individual experiments may take a long time on account of tedious crystallization. It will therefore be clear that the search for a good resolving agent for the separation of mixtures of enantiomers of a compound and the conditions under which good results are obtained is a time-consuming matter and the chance of success is unpredictable. Accordingly, there remains a need for an improved process for the resolution of eszopiclone that eliminates and reduces the problems of the prior art on a commercial scale in a convenient and cost efficient manner.